“Angelman syndrome” (AS) is a neurodevelopmental disorder characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, seizures, microcephaly and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, affinity for water, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of Angelman syndrome do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious.
Many of the characteristic features of Angelman syndrome result from the loss of function of a gene called UBE3A which encodes for ubiquitin protein ligase E3A (UBE3A) gene. (Kishino, T. et al. Nat Genet (1997) 12:385-395). People normally inherit one copy of the UBE3A gene from each parent. Both copies of this gene are turned on (active) in many of the body's tissues, however, in certain areas of the brain, only the copy inherited from a person's mother (the maternal copy) is active. This parent-specific gene activation is caused by a phenomenon called genomic imprinting. UBE3A is maternally imprinted in the brain, such that it is expressed nearly exclusively from the maternal chromosome while the paternal chromosome is epigenetically silenced. (Albrecht, U. et al., Nat Genet (1997) 17:75-78). If the maternal copy of the UBE3A gene is lost because of a chromosomal change or a gene mutation, a person will have no active copies of the gene in some parts of the brain.
Several different genetic mechanisms can inactivate or delete the maternal copy of the UBE3A gene. Most cases of Angelman syndrome (about 70 percent) occur when a segment of the maternal chromosome 15 containing this gene is deleted. In other cases (about 11 percent), Angelman syndrome is caused by a mutation in the maternal copy of the UBE3A gene.
Small nucleolar RNA host gene 14 (SNHG14), alternatively known as UBE3A-ATS, extends antisense into the UBE3A gene and thus plays a potential role in suppression of paternal UBE3A expression and imprinting. Much remains to be understood regarding how insufficiency of the protein product of UBE3A results in the observed neurodevelopmental deficits observed in Angelman Syndrome. Accordingly, there remains a need for improved and/or additional therapies for treating subjects diagnosed with Angelman Syndrome.